The present invention is directed to a two-step process for certain indol-2(3H)-ones (otherwise known as oxindoles, 2-oxindoles, 2-oxoindolines, or in their tautomeric form, as 2-hydroxyindoles), and to the intermediate 3,3-dibromoindol-2(3H)-ones employed in that process. Those of the present indol-2(3H)-ones which are monosubstituted on the benzene ring with C.sub.1 -C.sub.3)alkyl, C.sub.1 -C.sub.3)alkoxy or halogen are reported to have utility in the treatment of anxiety and tension (Molloy, U.S. Pat. No. 3,882,236). More particularly, all of the presently synthesized indol-2(3H)-ones are useful as intermediates in the synthesis of the analgesic/antiinflammatory 3-substituted 2-oxindole-1-carboxamides of Kadin, U.S. Pat. No. 4,556,672. Throughout the present text the products of the present invention are alternatively named as indol-2(3H)-ones (the more systematic name, based on Rigaudy et al. "IUPAC Nomenclature of Organic Chemistry", Pergammon Press, 1979, pp. 58, 172-173) and as oxindoles (a name finding common use in the literature).
Prior syntheses of present oxindoles have been reviewed, for example, by Sumpter et al., "The Chemistry of Heterocyclic Compounds", vol. 8, Weissberger, ed., Interscience Publishers, Inc., 1954, pp 134-138; and by Livingstone, in "Rodd's Chemistry of Carbon Compounds" 2nd. Edition, vol. 4, part A, S. Coffey, ed., Elsevier Scientific Publishing Co., 1973, pp. 448-451 and in "Supplements to the 2nd Edition of Rodd's Chemistry of Carbon Compounds", vol. 4, part A, M. F. Ansell, ed., Elsevier, 1984, pp. 440-441. For the most part by far, the synthetic methods for said oxindoles reflect cyclization of suitably substituted benzene derivatives. However, Beckett et al., Tetrahedron, vol. 24, pp. 6093-6109 (1968) prepared indol-2(3H)-one itself by the hydrogenation of an acidic ethanol solution of isatin over 10% Pd/C catalyst. Michaelis, Chem. Ber., vol. 30, pp. 2809-2821 (1897) and Coleman, Ann., vol. 248, pp. 114-120 (1888) converted N-alkylindoles to N-alkyloxindoles via 3,3-dibromo-N-alkyloxindoles, using sodium hypobromite for the first step and zinc/HCl reduction for the second.
Some of the present class of 3,3-dibromoindol-2(3H)-ones are known in the literature, but are of no specified utility. These are 3,3-dibromoindol-2(3H)-one itself and corresponding 5-bromo, 5,6-dibromo, 5,7-dibromo and 4,7-dimethoxy analogs; Sumpter et al., J. Am. Chem. Soc., vol. 67, pp. 1656-1657 (1945); DaSettimo, J. Org. Chem., vol. 39, pp. 1995-1998 (1974); and Parrick et al., Tetrahedron Lett., vol. 25, pp. 3099-3100 (1984). The earliest reference obtained these 3,3-dibromo compounds from the desired oxindole; the intermediate one by bromination of 2,3-dibromoindoles; and the latest by the action of N-bromosuccinimide (not pyridinium perbromide) on indoles or 3-bromoindoles.